Atypical trigeminocardiac reflex during intranasal dexmedetomidine sedation of a 6-month-old premature baby

Abstract

The trigeminocardiac reflex (TCR) is an established brainstem reflex leading to parasympathetic dysrhythmias—including haemodynamic irregularities, apnoea and gastric hypermotility—during stimulation of any sensory branches of the trigeminal nerve. Most of the clinical knowledge about TCR was gathered from general anaesthesia observations, not from procedural sedation.

We present a case of a 6-month-old premature baby experiencing the reflex twice under dexmedetomidine–propofol-sedation while undergoing ophthalmic and ear examination. This was interpreted as cross-over sensitisation between the facial and trigeminal cranial nerve (N V and N VII).

The present case demonstrates that different TCR subtypes can occur during the same anaesthetic procedure. Triggering TCR seems to be based on several factors and not just on a single stimulus as often presumed. Therefore, for premature babies, there is a risk for TCR under procedural sedation, and we recommend using glycopyrrolate as preventive treatment.

Background

Paediatric examination under anaesthesia (EUA) procedures in ophthalmology exposes children repeatedly to general anaesthesia (GA), with unknown consequences for cerebral maturation and development. This generates a substantial amount of anxiety for parents. To alleviate the presumed narcotic burden on small patients, we aim at periprocedural sedation using intranasal dexmedetomidine application as the primary agent. In this setting, anaesthesiologists need to balance the risk of small children’s GA against the risks of inadequate sedative depth. As this case exemplifies, the risk of haemodynamic complications inherent in manipulating the trigeminal sensory field can be altered by sedative drugs and preventive measures. Anaesthetists need to diligently gauge the balance for their small patients, especially former premature babies.

Here, we present the repeated occurrence of different subtypes of trigeminocardiac reflex (TCR) as a rare potential side effect of such EUA procedures in a procedural sedation.

Case presentation

We relate the case of a 6-month-old Caucasian boy (6 kg and 59 cm) being followed by ophthalmology for retinopathy of prematurity grade III who had already undergone laser ablation of both eyes 2 months previously. At birth, after 26 weeks and 2 days’ gestation, the patient had weighed 860 g (P40) and measured 33 cm (P30). He had a long history of intermittent intubations and continuous positive airway pressure ventilation due to surfactant deficiency and bronchopulmonary dysplasia, as well as late-onset sepsis. An initially patent arterial duct was determined to be closed in the meantime according to echocardiography. Normal cardiac function was confirmed. According to his parents, the initially problematic gastric reflux also abated completely. The infant (corrected age: 2 months and 23 days) weighed 6 kg and was well developed, with no symptoms or diseases other than the retinopathy.

On the day of the procedure, 18 µg of dexmedetomidine (3 µg/kg bodyweight) was administered intranasally as premedication spray on the ward using 1 mL insulin syringes and an LMA intranasal mucosal atomisation device. The child was left with his mother under the observation of a ward nurse, and no further monitoring was applied. 45 min later, he was brought to the anaesthesia anteroom in the arms of his mother, sleepy but easily arousable. After being placed on the operation stretcher, warmed by a Bair Hugger and warm drapes, the patient was monitored (ECG, continuous non-invasive blood pressure and SpO₂ sensor) and another intranasal dose of 24 µg of dexmedetomidine (4 µg/kg bodyweight) was administered. This latter dose was repeated after 30–40 min. In total, 48 µg of dexmedetomidine was given as procedural sedation. Both eyes received pupil-dilating drops (tropicamide 0.5% and phenylephrine 2.5%).

The following 15 min were spent with lights dimmed and low sensory input until a satisfactory sedative depth was achieved. For painful ocular/ear manipulations, a repeated dose of 4 mg (=0.7 mg/kg bodyweight) propofol 1% was given intravenously (four times in total). The ophthalmological examination battery included bulbar ultrasound, skiascopy, orthoptic testing, as well as retinal examination with photos being taken. ear-nose-throat/audio testing comprised microscopy of the external auditory duct, probing by a wire-loop probe and registration of auditory thresholds as well as auditory evoked potentials. Auditory excitatory input fell in a range up to 70 dB. Both examination batteries—including sedation period and monitoring—lasted 2 hours and 40 min.

Outcome and follow-up

Apart from periodic changes in respiration and cardiac pulse frequency typical for premature babies like the present infant, one short moment of desaturation to SpO₂ at 60% was observed during retinal photography, with increased camera weight pressing on the right eye. This was followed by spontaneous recovery within a few seconds (heart rate and arterial blood pressure were stable during this period). As the desaturation had no temporal relationship to a sedative bolus, this was interpreted as an oculorespiratory reflex, a subentity of TCR.

A sudden reduction in cardiac pulse frequency occurred 1 hour later during left retroauricular dermal peeling in preparation for the application of an electroencephalography electrode. The baby’s heart rate plummeted from 120 beats per minute to 50 beats per minute, followed by apnoea and desaturation below 90%. This spontaneously abated within 60 s of stopping the manipulation/stimulation. Based on clinical judgement, we labelled this as peripheral TCR. To prevent the reoccurrence of either reflex, glycopyrrolate in a dose of 25 µg (=4.2 µg/kg) was given. The remaining examination and sedation were uneventful. The patient recovered swiftly from the sedation with dexmedetomidine/propofol, without showing any postoperative deficits or complications, and was able to leave the hospital the same day.

Discussion

The classical definition of TCR includes a 20% decrease in heart rate and/or the occurrence of any sort of arrythmia or any other reflex end-organ involvement (apnoea and gastric hypermotility), but also a cause-effect relationship that is based on plausibility, reversibility, repetition and prevention.^{1 2} As presented here, this reflex is especially sensitive in neonates and infants, probably because of a higher resting vagal tone.³ Both necessary diagnostic criteria were fulfilled in the TCR occurrences.^{1 3}

Predominantly respiratory TCR is rarely described in the literature.² Fulfilment of strict and specific inclusion criteria for TCR excludes other differential diagnoses, such as smaller physiological variations of heart rate (HR) and mean arterial pressure (MABP) during anaesthesia or a pain reaction.^{1 2 4} Much of our knowledge about TCR, however, stems from clinical experience and research on the central part of the TCR.^{2 4} Recently, peripheral TCR—of which oculocardiac reflex is a part—has become better understood. The present case provides further insight into the physiology of this subtype (see figure 1). It is generally known that atropine and glycopyrrolate can decrease the prevalence of TCR but not prevent it.^{5 6} Vagotonic anaesthetics, such as dexmedetomidine and propofol in this current case, are known to increase incidence of the reflex, yet are not the sole explanation for TCR surfacing here (see figure 2).^{4 7}

Figure 1.

Peripheral sensitisation (authors: Schaller, Ugen). Based on the current case, several factors have been shown to influence the decrease of the threshold leading to a trigeminocardiac reflex (TCR) cascade. One central factor in this concept seems to be the (peripheral) sensitisation. Based on current knowledge, it is not clear whether age, as in this case, might be another contributing factor leading to a decrease in the threshold.

Figure 2.

Decrease of reflex threshold (authors: Schaller, Ugen). The present case showed that different factors are additionally involved in a decrease of the threshold needed to control the trigeminocardiac reflex (TCR). Whether age plays a role can only be assumed from the current knowledge. It appears that age makes drugs more prone to drug effects rather than serving as an independent factor.

Occurrence of TCR has never been described in the above described anaesthetic procedure, and this report may help prevent it.^{1 2} Actions taken after the first TCR in our case did not hinder a second TCR occurrence. The second occurrence was also unique, given that the area is innervated by the posterior auricular nerve, a sensory branch of the facial nerve. This nerve was not known to trigger TCR up until now. The phenomenon of such a cross-nerve sensitisation of trigeminal afferents leading to TCR was first described in 2010.⁸ However, this appears to be a first, unique case of cross-nerve sensitisation between two different cranial nerves. Cross-over sensitisation indicates increased responsiveness and reduced nerve excitation threshold to sensible nerve stimulation. It occurs after tissue injury and/or inflammation. In the current case, the ear examination may have led to stimulation of peripheral nerve endings and release of endogenous chemicals of the sensory part of facial nerve. These, in turn, may have activated and sensitised the peripheral sensory trigeminus nerve neurons resulting in cross-nerve sensitisation.⁹ To what extent immature myelination of the central nervous system could lead to cross-sensitisation remains speculative but goes in line with previous pathological observations.^{10 11} Proximity of pontine cranial nerve nuclei (V, VI, VII and IX) in general and the extension of the sensory trigeminal nucleus across midbrain, pons and medulla with its functional overlap for nerves V, VII, IX and X in particular, could be a point in favour for cross-sensitisation between facial and trigeminal sensory input.¹² Theoretically, this cascade might lead to an overshooting efferent vagal reflex.

This was true although stimuli arose from trigger points not represented in the neuroanatomical boundaries traditionally described for TCR. It thus seems that infants in the first 2 years of life are especially prone to the occurrence of the TCR.¹³

Topical application of medication (like lidocaine) to trigeminal innervated tissue is rarely described to prevent TCR episodes.⁶ Here phenylephrine, a selective alpha-1 stimulant, was used topically as mydriatics before/during undergoing ophthalmic EUA in dexmedetomidine sedation and probably facilitated the TCR. Both dexmedetomidine and propofol increase parasympathetic tone, mediated through the vagal nerve. Ineffective vagal modulation is a hallmark of lacking haemodynamic resilience of premature babies.¹⁴ The use of phenylephrine drops to dilate pupils has been tied to the occurrence of bradycardia, as well as to central effects on reflex control.^{13 15 16} There is ongoing discussion of whether the TCR is a physiological or a pathological reflex, and emergent evidence speaks for its physiological role. It is probable that developmental abnormalities or variants of the vital brainstem structures, such as hypoplasia, agenesis or neuronal immaturity of the arcuate, hypoglossus, pre-Bötzinger, cochlear, locus coeruleus or Kölliker-Fuse nuclei also played a role in this baby who was born prematurely.¹¹

In conclusion, we outline that anaesthesia or procedural sedation for ocular or facial procedures in premature babies must take the risks of TCR into account. Measures to counter TCR - like premedication with glycopyrrolate, atropine, analgosedation with ketamine or locoregional anaesthesia (ie, sub-Tenon’s block) to sever the reflex arch - ought to be part of procedural sedation. Anaesthetists need to be cognisant of the inherent risks of scheduled procedures (ie, eye examination), the inherent vagotonic abnormalities and vulnerabilities of the preterm child and the further increase in parasympathetic/vagal tonus induced by sedatives like dexmedetomidine or propofol.

Learning points.

• The present case demonstrates that different subtypes of trigeminocardiac reflex (TCR) can occur during the same procedure in babies under procedural sedation with dexmedetomidine and propofol.

• Anaesthetist must recognise the additive character of TCR-inducing circumstances like: prematurity and its ineffective vagal modulation, oculofacial surgical procedures and examinations, topical phenylephrine mydriatics and GABAergic or alpha-agonistic sedatives.

• TCR-countering measures like premedication with glycopyrrolate, emergency-medication with atropine and procedural sedation with more sympathotonic drugs like ketamine need to be considered. If vagal complications are known, interrupting the TCR arc by locoregional anaesthesia should be considered.

• The cross-nerve sensitisation presented here underlines that there must be other factors involved in triggering the afferent reflex arc, in addition to the classic mechanical, chemical or electrical stimulation.

• Our present case additionally demonstrates that the TCR action is a complex interaction with several contributing factors and that premature babies might have a special risk subgroup that was not yet known.

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